Process for the enantioselective synthesis of propargyl alcohol derivatives of R configuration from the racemic mixtures thereof

Abstract

The invention relates to a novel process for synthesizing organic compounds of general formula (I): said process may be carried out on an industrial scale and makes it possible to obtain from a mixture of racemic alcohols of formula (II), the corresponding chiral alcohols of R configuration, in a high chemical yield.

1. Process for synthesizing organic compounds of R configuration of general formula (I): 
                 
 
       in which:
 R 1  represents a hydrogen atom, an alkyl radical containing from 1 to 6 carbon atoms, an aryl radical, a halogen atom or a radical —OR 3 , R 3  having the meaning given below,  
 R 2  represents a hydrogen atom or an alkyl radical containing from 1 to 6 carbon atoms,  
 R 3  represents a hydrogen atom or an alkyl radical containing from 1 to 6 carbon atoms,  
 said process being characterized in that it comprises the following steps: 
 a) placing a compound of formula (II): 
                 
 
  in contact with an effective amount of lipase in the presence of an acylating agent and a solvent to obtain a mixture of corresponding R acetate and S alcohol,  
 b) treating the mixture of R acetate and S alcohol with a dialkyl azodicarboxylate in the presence of trialkyl or triaryl phosphines and a nucleophilic compound so as to convert the alcohol into R acetate by inversion of configuration,  
 c) obtaining the corresponding R alcohol by transesterification, in the presence of methanol and sodium carbonate, followed by a crystallization, and then  
 d) coupling the alcohol thus obtained with the compound of formula (III): 
                 
 
 
 
       in which:
 X represents a halogen atom,  
 R 1  has the same meaning as above,  
 R 2  represents a hydrogen atom or an alkyl radical containing from 1 to 6 carbon atoms, in this latter case, the ester possibly undergoing a saponification reaction to give the compound of formula (I) with R 2 ═H.  
 
     
     
       2. Process according to  claim 1 , characterized in that the lipase is chosen from lipases obtained from  Pseudomonas.    
     
     
       3. Process according to  claim 1 , characterized in that the lipase is  Pseudomonas capacia  lipase. 
     
     
       4. Process according to  claim 1 , characterized in that the acylating agent is chosen from vinyl acetate, vinyl propionate, vinyl butyrate, and vinyl valerate. 
     
     
       5. Process according to  claim 1 , characterized in that the acylating agent is vinyl acetate. 
     
     
       6. Process according to  claim 1 , characterized in that the solvent is chosen from alkanes, ethyl acetate, chlorinated alkanes, ether solvents, and aromatic solvents. 
     
     
       7. Process according to  claim 1 , characterized in that the solvent is heptane. 
     
     
       8. Process according to  claim 1 , characterized in that the dialkyl azodicarboxylate is chosen from diethyl azodicarboxylate and diisopropyl azodicarboxylate. 
     
     
       9. Process according to  claim 1 , characterized in that the dialkyl azodicarboxylate is diisopropyl azodicarboxylate. 
     
     
       10. Process according to  claim 1 , characterized in that the trialkyl or triaryl phosphine is chosen from triphenylphosphine and tri-n-butylphosphine. 
     
     
       11. Process according to  claim 1 , characterized in that the trialkyl or triaryl phosphine is tri-n-butylphosphine. 
     
     
       12. Process according to  claim 1 , characterized in that the nucleophilic compound is chosen from carboxylic acids. 
     
     
       13. Process according to  claim 1 , characterized in that the nucleophilic compound is acetic acid. 
     
     
       14. Process according to  claim 1 , characterized in that step a) is performed at a temperature of between 10 and 100° C. 
     
     
       15. Process according to  claim 1 , characterized in that step a) is performed at a temperature of between 35 and 40° C. 
     
     
       16. Process according to  claim 1 , characterized in that step a) is performed for a duration of between 10 hours and 10 days. 
     
     
       17. Process according to  claim 1 , characterized in that step a) is performed for a duration of between 1 and 2 days. 
     
     
       18. Process according to  claim 1 , for the synthesis of propargyl alcohols of R configuration and of formula (Ia) below: 
                 
 
       said process being characterized in that it comprises the following steps:
 a) placing a compound of formula (IIa): 
                 
 
  in contact with an effective amount of lipase obtained from  Pseudomonas  in the presence of of vinyl acetate as acylating agent and heptane as solvent, to form the corresponding R acetate and S alcohol;  
 b) treating the mixture of R acetate and S alcohol with a diisopropyl azodicarboxylate in the presence of tri-n-butylphosphine and acetic acid so as to obtain the R acetate by inversion of configuration of the S alcohol;  
 c) obtaining the optically pure corresponding R alcohol by transesterification in the presence of methanol and sodium carbonate, followed by a crystallization;  
 d) coupling, via a standard chemical reaction, the compound of formula (IIIa) below; and 
                 
 
 e) performing a saponification reaction to obtain the compound of formula (Ia):